This competitive renewal seeks continued support for a program project which, over its history, has made a dedicated effort to better understand the complex pathobiology of human traumatic brain injury (TBI) and, based upon such understanding, develop more rational therapeutic strategies. The theme of this application centers on the role of receptor-mediated neuronal injury and its relation to the release of excessive excitatory neurotransmitters. In the laboratory, this application moves on the premise that an initial, excessive release of excitatory neurotransmitters, elicited by the TBI, causes receptor-mediated injury, leading to neuronal dysfunction and/or death. In this vane, one laboratory effort assesses the damaging consequences of increased neurotransmitter release in TBI to determine if transmitter-related neurotoxicity can be amplified by synergetic mechanisms. Another laboratory project examines the consequences of this excessive transmitter release in terms of excessive receptor activation to elicit the altered coupling of the neurotransmitter receptors to their effector molecules. Another laboratory component examines the role of these abnormal receptor-mediated interactions by examining their long-term consequences in terms of cognitive dysfunction. Lastly, in the lab, the concept of receptor-mediated change will be considered not only in the context of generalized neuroexcitation but also in the context of diffuse injury, complicated by focal insult/deafferentation. In the clinical setting, efforts will be made to better document the role of excitatory neurotransmitters in the pathobiology of TBI. Intracerebral microdialysis will be employed in patients to measure local excitatory amino acid levels as well as ionic flux and lactate/pyruvate ratios in varied brain regions. These microdialysis studies will be conducted in concert with studies of CBF and ICP changes. These CBF changes will be provided as an extension of another project which will examine the genesis of the altered early ischemia seen after TBI. Lastly, in this same patient population, studies will be performed to better elucidate the mechanisms responsible for the brain swelling and subsequent ICP rise seen after brain injury. Efforts will be made to determine if brain edema is derived primarily from cellular swelling due to either ischemic or neurotoxic processes. Collectively, we believe that all of the above projects are logical outgrowths of our previous research efforts. They explore important issues directly relevant to the pathobiology of human TBI and most likely will suggest new therapeutic approaches for the more rational treatment of human TBI.